Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

The current invention is directed to compositions comprising a plurality
of particles including nanoshells or a medical device with a coating
including nanoshells allowing for triggered drug release. Methods of
treatment with such compositions are also included.

Claims:

1. A composition for controlled release of a drug comprising:a plurality
of particles comprising:an amorphous or semi-crystalline polymer with a
glass transition temperature as plasticized under physiological
conditions from about 40.degree. C. to about 60.degree. C., or a
semi-crystalline polymer having a degree of crystallinity of at least 25%
with a melting temperature, as plasticized under physiological
conditions, from about 40.degree. C. to about 60.degree. C.;a drug;
andone or more nanoshells capable of producing heat upon exposure to
electromagnetic radiation, a fluctuating magnetic field, or a microwave
field;whereinsubstantially all of the individual particles of the
plurality include one or more of the nanoshells.

2. The composition of claim 1, wherein upon exposure to electromagnetic
radiation, a fluctuating magnetic field, or a microwave field the
nanoshells produce sufficient heat to raise the temperature of the
polymer above its glass transition temperature or its melting
temperature.

3. The composition of claim 1, wherein the glass transition temperature or
the melting temperature of the polymer is from about 40.degree. C. to
about 50.degree. C.

4. The composition of claim 1, wherein the average diameter of the
particles is about 50 nanometers to about 10 micrometers.

5. The composition of claim 1, wherein the nanoshells comprise gold.

6. The composition of claim 5, wherein the average diameter of the
nanoshells is about 15 nanometers to about 200 nanometers.

13. The composition of claim 1, wherein the composition comprises at least
two drugs, the two drugs comprising a statin and an anti-inflammatory
drug, or a statin and fenofibrate.

14. The composition of claim 13, wherein the composition is capable of
releasing both drugs at an increased release rate after the composition
is exposed to electromagnetic radiation, a fluctuating magnetic field, or
a microwave field

15. A method comprising:administering to a patient in need thereof the
composition of claim 1; andapplying a fluctuating magnetic field, a
microwave field, or an electromagnetic radiation to the composition.

16. The method of claim 15, wherein administering the composition
comprises systemic or local administration.

18. The method of claim 16, wherein local administration comprises
administration by a catheter, a coated balloon catheter, a
needle-injection catheter, a porous balloon catheter, local needle
injection, implantation of a coated stent, implantation of a
biodegradable stent, implantation of a biodegradable implant, or any
combination thereof.

19. The method of claim 15, wherein the fluctuating magnetic field, the
microwave field, or the electromagnetic radiation is applied outside the
patient's body.

20. The method of claim 15, wherein the fluctuating magnetic field, the
microwave field, or the electromagnetic radiation is applied inside the
patient's body.

21. The method of claim 20, where application within a patient's body
comprises using a catheter.

22. The method of claim 15, wherein patient is need of treatment for a
disease or condition selected from the group consisting of
atherosclerosis, vulnerable plaque, restenosis, peripheral vascular
disease, small vessel bifurcations and cancer.

23. An implantable medical device, comprising:a device body having an
outer surface;an optional primer layer disposed over the outer surface;
anda coating comprising:an amorphous or semi-crystalline polymer with a
glass transition temperature as plasticized under physiological
conditions from about 40.degree. C. to about 60.degree. C., or a
semicrystalline polymer having a degree of crystallinity of at least 25%
with a melting temperature, as plasticized under physiological
conditions, from about 40.degree. C. to about 60.degree. C.;a drug; anda
plurality of nanoshells capable of producing heat upon exposure to
electromagnetic radiation, a fluctuating magnetic field, or a microwave
field;whereinthe coating comprises one or more layers disposed over the
outer surface or over the primer layer, if opted for.

24. The device of claim 23, wherein the coating comprisesa first coating
layer disposed over the outer surface or the primer layer if opted for,
the first coating layer comprising a drug;and a second coating layer,
disposed over the first coating layer, comprising the polymer and the
nanoshells.

[0002]Modulated drug delivery refers to matching the release profiles of
drugs to the physiological requirements of the patient. This type of
controlled delivery is useful for treating diseases that affect the
homeostatic functions of the body, such as diabetes mellitus. Insulin
therapy for diabetes requires a low baseline release of the drug, with
peaks after the ingestion of food.

[0003]Various methods of accomplishing modulated in vivo drug delivery
have been described in the literature. Mechanical pumps are one type of
device that is commonly employed. Another method that has been examined
is the use of ultrasound to rupture microcapsules or strip a layer of
material from a drug-containing polymer matrix to alter drug release.
Potential problems with such ultrasound techniques include concurrent
rupture of cells at high levels of insonation power and concern about the
long term safety of repetitive exposure of body tissues to ultrasonic
energy.

[0004]Certain temperature sensitive hydrophilic polymer gels (hydrogels)
have been described as another means of modulating drug delivery. When
the temperature of the polymer is raised above its lower critical
solution temperature (LCST), the hydrogel undergoes a reversible phase
transition that results in the collapse of the hydrogel structure. The
hydrogel collapse forces soluble materials held within the hydrogel
matrix to be expelled into the surrounding solution. An impediment to the
development of temperature-sensitive materials into clinically useful
modulated drug delivery devices has been the lack of satisfactory means
for altering the temperature of the implanted device.

[0006]An aspect of the present invention is a composition for controlled
release of a drug comprising:

[0007]a plurality of particles comprising: [0008]an amorphous or
semi-crystalline polymer with a glass transition temperature as
plasticized under physiological conditions from about 40° C. to
about 60° C., or a semi-crystalline polymer having a degree of
crystallinity of at least 25% with a melting temperature, as plasticized
under physiological conditions, from about 40° C. to about
60° C.; [0009]a drug; and [0010]one or more nanoshells capable of
producing heat upon exposure to electromagnetic radiation, a fluctuating
magnetic field, or a microwave field;wherein substantially all of the
individual particles of the plurality include one or more of the
nanoshells.

[0011]In an aspect of this invention, the average diameter of the
particles is about 50 nanometers to about 10 micrometers.

[0012]In an aspect of this invention, the polymer comprises a coating on
the particles.

[0013]In an aspect of this invention, the particles are composed entirely
of a polymer matrix.

[0014]Another aspect of this invention is an implantable medical device,
comprising:

[0015]a device body having an outer surface;

[0016]an optional primer layer disposed over the outer surface; and

[0017]a coating comprising: [0018]an amorphous or semi-crystalline
polymer with a glass transition temperature as plasticized under
physiological conditions from about 40° C. to about 60° C.,
or a semicrystalline polymer having a degree of crystallinity of at least
25% with a melting temperature, as plasticized under physiological
conditions, from about 40° 0 C. to about 60° C.; [0019]a
drug; and [0020]a plurality of nanoshells capable of producing heat upon
exposure to electromagnetic radiation, a fluctuating magnetic field, or a
microwave field;wherein the coating comprises one or more layers disposed
over the outer surface or over the primer layer, if opted for.

[0021]In an aspect of this invention, the coating comprises a first
coating layer disposed over the outer surface or the primer layer if
opted for, the first coating layer comprising a drug; and a second
coating layer, disposed over the first coating layer, comprising the
polymer and the nanoshells.

[0022]In an aspect of this invention, upon exposure to electromagnetic
radiation, a fluctuating magnetic field, or a microwave field the
nanoshells produce sufficient heat to raise the temperature of the
polymer above its glass transition temperature or its melting
temperature.

[0023]In an aspect of this invention, the glass transition temperature or
the melting temperature of the polymer is from about 40° C. to
about 50° C.

[0024]In an aspect of this invention, the nanoshells comprise gold.

[0025]In an aspect of this invention, the average diameter of the
nanoshells is about 15 nanometers to about 200 nanometers.

[0030]In an aspect of this invention, the composition comprises at least
two drugs, the two drugs comprising a statin and an anti-inflammatory
drug, or a statin and fenofibrate, and in a further aspect of this
invention, the composition is capable of releasing both drugs at
respective optimal release rates modulated when the composition is
exposed to electromagnetic radiation, a fluctuating magnetic field, or a
microwave field.

[0031]Another aspect of this invention is a method comprising:
administering to a patient in need thereof the plurality of particles;
and applying a fluctuating magnetic field, a microwave field, or an
electromagnetic radiation to the composition.

[0032]In an aspect of this invention, administering the plurality of
particles comprises systemic or local administration.

[0033]In an aspect of this invention, systemic administration comprises
intravenous injection, intramuscular injection, or injection into the
bone marrow.

[0034]In an aspect of this invention, local administration comprises
administration by a catheter, a coated balloon catheter, a
needle-injection catheter, a porous balloon catheter, local needle
injection, implantation of a coated stent, implantation of a
biodegradable stent, implantation of a biodegradable implant, or any
combination thereof.

[0035]Another aspect of this invention is a method comprising implanting
into a patient in need thereof an implantable medical device as described
above, and applying to the device a fluctuating magnetic field, a
microwave field, or an electromagnetic radiation.

[0036]In an aspect of this invention, the fluctuating magnetic field, the
microwave field, or the electromagnetic radiation is applied outside the
patient's body.

[0037]In an aspect of this invention, the fluctuating magnetic field, the
microwave field, or the electromagnetic radiation is applied inside the
patient's body.

[0038]In an aspect of this invention, application within a patient's body
comprises using a catheter.

[0039]In an aspect of this invention, the patient is in need of treatment
for a disease or condition selected from the group consisting of
atherosclerosis, vulnerable plaque, restenosis, peripheral vascular
disease, small vessel bifurcations and cancer.

[0041]FIG. 2 depicts an exemplary embodiment of particles of the present
invention.

[0042]FIG. 3 depicts a second exemplary embodiment of particles of the
present invention.

[0043]FIG. 4 depicts a third exemplary embodiment of particles of the
present invention.

[0044]FIG. 5 depicts a fourth exemplary embodiment of particles of the
present invention.

[0045]FIG. 6 is a depiction of an expanded balloon at the end of a
catheter.

[0046]FIG. 7 is a depiction of an expanded multi-balloon at the end of a
catheter.

[0047]FIGS. 8A and 8B are depictions of an injection catheter.

[0048]FIG. 9 is a depiction of an exemplary embodiment of an injection
balloon and catheter assembly.

DISCUSSION

[0049]Use of the singular herein includes the plural and vice versa unless
expressly stated to be otherwise. That is, "a" and "the" refer to one or
more of whatever the word modifies. For example, "a drug" may refer to
one drug, two drugs, etc. Likewise, "the polymer" may mean one polymer or
a plurality of polymers. By the same token, words such as, without
limitation, "drugs" and "polymers" refer to one drug or polymer as well
as to a plurality of drugs or polymers unless it is expressly stated or
obvious from the context that such is not intended.

[0050]As used herein, unless specified otherwise, any words of
approximation such as without limitation, "about," "approximately,"
"essentially," "substantially" and the like mean that the element so
modified need not be exactly what is described but can vary from the
description by as much as ±15% without exceeding the scope of this
invention.

[0051]As used herein, any ranges presented are inclusive of the
end-points. For example, "a temperature between 10° C. and
30° C." or "a temperature from 10° C. to 30° C."
includes 10° C. and 30° C., as well as any temperature in
between.

[0052]As used herein, the use of "preferred," "preferably," "more
preferred," and the like to modify an aspect of the invention refers to
preferences as they existed at the time of filing of the patent
application.

[0053]As used herein, a "polymer" is a molecule made up of the repetition
of a simpler unit, herein referred to as a constitutional unit. The
constitutional units themselves can be the product of the reactions of
other compounds. A polymer may comprise one or more types of
constitutional units. As used herein, the term polymer refers to a
molecule comprising 2 or more constitutional units. Polymers may be
straight or branched chain, star-like or dendritic, or one polymer may be
attached (grafted) onto another. Polymers may have a random disposition
of constitutional units along the chain, the constitutional units may be
present as discrete blocks or segments, or constitutional units may be so
disposed as to form gradients of concentration along the polymer chain.
Polymers may be cross-linked to form a network.

[0054]As used herein, "copolymer" refers to a polymer which includes more
than one type of constitutional unit.

[0055]As used herein, a "polymer segment" refers to a polymeric species
that comprises a part of a larger polymer. For example for a block
copolymer of constitutional units x, y, and z, a string of x
constitutional units may constitute a segment. The segment itself may
also be considered a polymer although it is part of a larger molecule.
The segment may be made up of more than one type of constitutional unit.
Thus they are referred to herein as "polymer segments" or sometime simply
"segments." The terms are used interchangeably herein.

[0056]As used herein, "biocompatible" refers to a polymer or other
material that both in its intact, that is, as synthesized, state and in
its decomposed state, i.e., its degradation products, is not, or at least
is minimally, toxic to living tissue; does not, or at least minimally and
reparably, injure(s) living tissue; and/or does not, or at least
minimally and/or controllably, cause(s) an immunological reaction in
living tissue.

[0057]As used herein, the terms "biodegradable", "bioerodable",
"bioabsorbable," "degraded," "eroded," "absorbed," and "dissolved," are
used interchangeably, and refer to a substance that is capable of being
completely or substantially completely, degraded, dissolved, and/or
eroded over time when exposed to physiological conditions (pH,
temperature, enzymes and the like), and can be gradually eliminated by
the body, or that can be degraded into fragments that can pass through
the kidneys. Conversely, "biostable" refers to a substance that is not
biodegradable, etc.

[0058]The glass transition temperatures, Tg, is the temperature at
which an amorphous polymer or amorphous segment of a polymer changes
mechanical properties from those of a rubber (i.e., elastic) to those of
a glass (brittle). The Tg of a given polymer/polymer segment depends
on its thermal history as well as the method used to measure it. For the
purposes of this invention, any reference to a Tg is understood to
be that obtained by differential scanning calorimetry (DSC). The chemical
structure of the polymer heavily influences Tg by affecting chain
mobility. Below the Tg the polymeric molecules have very little
rotational or translational freedom, i.e., they are unable to rotate or
move easily or very far in relation to one another. Above Tg,
relatively facile segmental motion becomes possible and the polymer
chains are able to move around and slip by one another.

[0059]Plasticization of a polymer refers to lowering the Tg of the
polymer by adding a lower molecular weight material to a polymer.
Exemplary plasticizers include, without limitation, phthalate,
trimellitate, sebacate and maleate esters, epoxidized vegetable oils,
sulfonamides, organophosphates, glycols and polyethers.

[0060]As used herein, a material that is described as a layer, a film, a
coating, or a coating layer "disposed over" a substrate refers to
deposition of the material directly or indirectly over at least a portion
of the surface of that substrate. "Directly deposited" means that the
material is applied directly to the surface of the substrate. "Indirectly
deposited" means that the material is applied to an intervening layer
that has been deposited directly or indirectly over the substrate. The
terms "layer," "film," "coating" and "coating layer" are used
interchangeably herein. Unless the context clearly indicates otherwise, a
reference to a layer, film, coating, or coating layer refers to such
covering all, or substantially all, of the surface over which it is
disposed, directly or indirectly.

[0061]As used herein, a "coating formulation" refers to the mixture of
substances disposed over a substrate. If substances are dissolved or
dispersed in a solvent to form a "coating solution," and the coating
solution is disposed over a substrate followed by removal of the solvent,
the solvent is not part of the "coating formulation." However, the layer
deposited may contain small amounts of residual solvent.

[0062]As used herein, a "primer layer" refers to a coating consisting of a
material such as, without limitation, a polymer, that exhibits good
adhesion to the material of which the substrate is manufactured, and also
good adhesion to whatever material is to be coated on the substrate.
Thus, a primer layer serves as an adhesive intermediary layer between a
substrate and materials to be carried by the substrate and is, therefore,
applied directly to the substrate. Preferred substrates are medical
device bodies, and nanoshells. Non-limiting examples of primers for use
with device bodies, and potentially for use with nanoshells, include
silanes, titanates, zirconates, silicates, parylene, polyacrylates and
polymethacrylates.

[0063]As used herein, a "drug" refers to any substance that, when
administered in a therapeutically effective amount to a patient suffering
from a disease or condition, has a therapeutic beneficial effect on the
health and well-being of the patient. A therapeutic beneficial effect on
the health and well-being of a patient includes, but it not limited to:
(1) curing the disease or condition; (2) slowing the progress of the
disease or condition; (3) causing the disease or condition to retrogress;
or, (4) alleviating one or more symptoms of the disease or condition.

[0064]As used herein, a drug also includes any substance that when
administered to a patient, known or suspected of being particularly
susceptible to a disease, in a prophylactically effective amount, has a
prophylactic beneficial effect on the health and well-being of the
patient. A prophylactic beneficial effect on the health and well-being of
a patient includes, but is not limited to: (1) preventing or delaying
on-set of the disease or condition in the first place; (2) maintaining a
disease or condition at a retrogressed level once such level has been
achieved by a therapeutically effective amount of a substance, which may
be the same as or different from the substance used in a prophylactically
effective amount; or, (3) preventing or delaying recurrence of the
disease or condition after a course of treatment with a therapeutically
effective amount of a substance, which may be the same as or different
from the substance used in a prophylactically effective amount, has
concluded.

[0065]As used herein, "drug" also refers to pharmaceutically acceptable,
pharmacologically active derivatives of those drugs specifically
mentioned herein, including, but not limited to, salts, esters, amides,
and the like. Substances useful as diagnostics are also encompassed by
the term "drug."

[0066]As used herein, an "organic solvent" is a fluid the chemical
composition of which includes carbon atom(s). The fluid may be liquid,
gaseous or in a supercritical state. An organic solvent herein may be a
blend of two or more such fluids.

[0067]As used herein, a "particle" simply refers to a macroscopic fragment
of material of no particular shape composed of an agglomeration of
individual molecules of one or more compounds. For the purposes of this
disclosure, a particle can range in size from less than a one tenth of a
nanometer to several millimeters.

[0068]As used herein, the "average diameter" of a plurality of particles
refers to diameters determined by dynamic light scattering (DLS), also
referred to as photo correlation spectroscopy. Dynamic light scattering
determines the hydrodynamic diameter (Stokes diameter) based on diffusion
measurements, and includes solvent associated with the particle. For
non-spherical particles, the reported "diameter" is actually the
effective diameter of a sphere with the equivalent hydrodynamic radius.
This mean hydrodynamic diameter obtained from DLS is close to the
volume-average diameter. A non-limiting example of a method for
determining average diameters is International Standards Organization
(ISO) 13321.

[0069]There are a number of other ways of representing the average
diameter of a group of particles. The average diameter can be a number
average diameter, where the number average
diameter=Σidini/Σini where ni
represents the number of particles with a diameter represented by
di. The surface area average diameter is determined by
(Σifidi2)1/2, and the volume average
diameter is determined by (Σifidi3)1/3,
where fi is ni/Σini. The volume average is
greater than the surface area average diameter, which is greater than the
number average diameter. The mass or weight average diameter is the same
as the volume average diameter if the density of all of the particles is
the same. For the purposes of this invention, any manner of average
diameter determination can be used so long as the result is correlated
with that obtained by DLS, the technique used herein.

[0070]Particles are generally polydisperse, i.e., not all the same size.
One measure of polydispersity is the ratio D90/D10. D90 and D10 are the
diameters below which 90% and 10% of the particles fall for a number
average diameter, or 90% or 10% of the surface area of the particles fall
for a surface area average diameter, and the like. As used herein, unless
specified otherwise, the D90 and D10 are the diameters taken from the
cumulative particle size distribution as determined by DLS.

[0071]As used herein, "nano-particles" refer to particles with an average
diameter from 1 nm to 10 μm.

[0072]As used herein, "micro-particles" refer to particles with an average
diameter from 10 μm to about 1000 μm.

[0073]As used herein, "burst release" refers to the release of a drug from
a drug delivery system within a very short time, or a large increase in
drug release within a very short time.

[0074]As used herein, "release rate" refers to the amount of drug released
from a drug delivery system per unit of time, for example without
limitation 0.1 mg per hour (0.1 mg/hr) or 100 mg per day.

[0075]As used herein, "release duration," refers to the total time over
which a drug is released in a therapeutically effective amount from a
drug delivery system. For example without limitation, a drug release
duration of 1 hour, 72 hours or 6 months means that a therapeutically
effective amount of the drug is released over that time period.

[0076]As used herein, any measurement of drug release, for example without
limitation, release rate or release duration, refers to the an in vitro
measurement using a United States Pharmacopeia Type VII apparatus and
porcine serum at a temperature of 37° C., with sodium azide
optionally added (for example at 0.1% w/v).

[0077]A polymer matrix refers to a three dimensional construct in which
one or more polymers forms a continuous phase. A polymer matrix may
include other materials, non-limiting examples of which are drugs and
plasticizers. Other materials may be dispersed within the matrix,
homogeneously or substantially homogeneously, to form a separate phase.

[0078]The "percolation threshold" is the point at which domains of a
discrete phase in a multiple phase system begin to connect and form an
interconnected network within the continuous phase. Percolation
thresholds are generally expressed as a volume fraction and are a
function of the domain size and shape for each of the phases in the
multiple phase system.

[0079]As used herein, an "implantable medical device" refers to any type
of appliance that is totally or partly introduced, surgically or
medically, into a patient's body or by medical intervention into a
natural orifice, and which is intended to remain there after the
procedure. The duration of implantation may be essentially permanent,
i.e., intended to remain in place for the remaining lifespan of the
patient; may be until the device biodegrades; or may be until it is
physically removed. Examples of implantable medical devices include,
without limitation, implantable cardiac pacemakers and defibrillators;
leads and electrodes for the preceding; implantable organ stimulators
such as nerve, bladder, sphincter and diaphragm stimulators, cochlear
implants; prostheses, vascular grafts, self-expandable stents,
balloon-expandable stents, stent-grafts, grafts, artificial heart valves,
foramen ovale closure devices, cerebrospinal fluid shunts, and
intrauterine devices. An implantable medical device specifically designed
and intended solely for the localized delivery of a drug is within the
scope of this invention. Implantable medical devices can be made of
virtually any material including metals and/or polymers.

[0080]One form of implantable medical device is a "stent." A stent refers
generally to any device used to hold tissue in place in a patient's body.
Particularly useful stents, however, are those used for the maintenance
of the patency of a vessel in a patient's body when the vessel is
narrowed or closed due to diseases or disorders including, without
limitation, tumors (in, for example, bile ducts, the esophagus, the
trachea/bronchi, etc.), benign pancreatic disease, coronary artery
disease such as, without limitation, atherosclerosis, carotid artery
disease, peripheral arterial disease (PAD), restenosis and vulnerable
plaque. For treatment of PAD, stents may be used in peripheral arties
such as the superficial femoral artery (SFA).

[0081]As used herein a "device body" refers to an implantable medical
device in a fully formed utilitarian state with an outer surface to which
no coating or layer of material different from that of which the device
itself is manufactured has been applied. By "outer surface" is meant any
surface however spatially oriented that is in contact with bodily tissue
or fluids. A common example of a "device body" is a BMS, i.e., a bare
metal stent, which, as the name implies, is a fully-formed usable stent
that has not been coated with a layer of any material different from the
metal of which it is made on any surface that is in contact with bodily
tissue or fluids. Of course, device body refers not only to BMSs but to
any uncoated device regardless of what it is made of.

[0082]As used herein, a "catheter" is a thin, flexible tube for insertion
into the body. Catheters may be used to remove or introduce fluid. One
form of catheter is a vascular catheter. A vascular catheter is a thin,
flexible tube with a manipulating means at one end, referred to as the
proximal end, which remains outside the patient's body, and an operative
device at or near the other end, called the distal end, which is inserted
into the patient's artery or vein. A vascular catheter may have a balloon
disposed on the distal end, and/or may be used to delivery a stent to an
artery. Another form of catheter is a urinary catheter.

[0083]As used herein, a "balloon" refers to the well-known in the art
device, usually associated with a vascular catheter, that comprises a
relatively thin, elastomeric material that when positioned at a
particular location in a patient's vessel can be expanded or inflated to
an outside diameter that is essentially the same as the inside or luminal
diameter of the vessel in which it is placed.

[0084]The present invention is directed to drug delivery compositions
allowing for triggered drug release, and methods of using such
compositions. The drug delivery compositions comprise a polymer, a drug,
and nanoshells. The polymer, drug and nanoshells may be included in a
coating and/or in particles. The nanoshells are capable of heating up as
a result of absorption of electromagnetic radiation, or exposure to a
fluctuating magnetic field. Due to heating of the nanoshells, the polymer
is heated to a temperature above its glass transition temperature or its
melt temperature resulting in a change in the diffusivity of the drug,
and thus impacting drug release from the coating or from the particles.

[0085]Nanoshells are particles with a core and a shell or a core and two
or more layers. FIG. 1 depicts an exemplary nanoshell which has a core
110 and a shell 120 where the thickness of the shell is exaggerated. The
shell is a conducting material such as a metal, and the core is
preferably non-conducting. However, it is only required that at least one
layer has a lower dielectric constant than the adjacent inner layer or
the adjacent core.

[0086]These nanoshells of this invention undergo a phenomenon known as
plasmon resonance which is the collective coupling of the electrons in
the metal of the shell with the incident electromagnetic radiation. The
plasmon resonance can be dominated by absorption or scattering of the
electromagnetic radiation. The wavelength at which the maximum plasmon
resonance occurs can be "tuned" by altering the ratio of the shell
thickness to the core thickness, or the ratio of the layer thicknesses.
In general, for a given core radius, the wavelength at which maximum
resonance occurs becomes longer as the shell becomes thinner. The ratio
of shell thickness to core radius may vary from 10 to 10-3. The
wavelength at which plasmon resonance occurs may range from 400 nm to 20
μm. A non-limiting example of an operable nanoshell for the purposes
of this invention is one with a core diameter in the range of about 55
and about 210 nm with a gold shell in the range of about 5 and about 25
nm (see, e.g., Oldenburg S. J., et al., Applied Physics Letters; Vol.
75(19):2897-2899 (1999); Oldenburg S. J., et al., Chemical Physics
Letters 288:243-247 (1998)).

[0087]The core may be composed of dielectric materials or semiconductor
materials. Exemplary but non-limiting core materials include colloidal
silica, silicon dioxide, titanium dioxide, polymethyl methacrylate
(PMMA), polystyrene, and gold sulfide, and semiconductor materials such
as, without limitation, CdSe, CdS, or GaAs. The shell material is
preferably a conducting material, such as a metal, e.g. without
limitation, the noble metals and coinage metals, or an organic conducting
material such as polyacetylene and doped polyanaline. More specifically
the shell may include, but is not necessarily limited to, metals such as
gold, silver, copper, platinum, palladium, lead, iron, biodegradable
metals such as magnesium, zinc, calcium, or tungsten, and alloys and
combinations thereof.

[0088]For use in the present invention, nanoshells with plasmon resonance
wavelengths in the range of 900 nm to 1200 nm or in the near-infrared
from 650 nm and 900 nm are preferred. The near-infrared spectrum between
650 nm and 900 nm in particular readily permeates living tissue.

[0089]The nanoshells may be 5-500 nm in diameter, preferably about 10 to
about 300 nm, and more preferably about 15 to about 200 nm. The outer
shell layer of the nanoshells may have a thickness in the range between
about 1 nm and about 100 nm. The nanoshells can be any shape such as,
without limitation, spherical, rod or fiber shaped. However, a spherical
or nearly spherical shape is preferred. It is preferable that the
nanoshells have a relatively low polydispersity. In some embodiments, the
D90/D10 of the nanoshells is not more than 5, not more than 4, not more
than 3, or not more than 2.

[0090]In a preferred embodiment, the shell is silver or gold and the core
is silica.

[0091]More details on the nanoshells are described in U.S. Pat. No.
6,685,986, incorporated by reference herein, which includes a method of
manufacturing nanoshells in Examples I-V. Other relevant patents and
patent application publications include U.S. Pat. Nos. 6,660,381,
6,699,724, and U.S. Patent application publications 2002/0061363,
2002/0132045, 2002/0187347, 2002/0164064, and 2005/0056118, all of which
are incorporated by reference herein.

[0092]In other embodiments, a different form of nanoshells is used. This
form of nanoshell has a core or shell of iron, iron oxide or other
materials that heat up when exposed to a fluctuating magnetic field. In
addition to iron and iron oxide, lanthanides such as samarium,
gadolinium, europium and terbium, elements such as tantalum and
molybdenum, and combinations, mixtures, and alloys thereof, may be used.

[0093]Compositions of the present invention include particles and coatings
containing nanoshells. The particles are microparticles or nanoparticles
comprising a polymer. Non-limiting exemplary embodiments of particles are
illustrated in FIGS. 2-5. In the embodiments illustrated in FIGS. 2A, 3A,
and 4A, a polymer matrix surrounds a nanoshell. In the embodiments
illustrated in FIGS. 2B, 3B, and 4B, one or more nanoshells are embedded
in a polymer matrix. In FIGS. 2A and 2B, the polymer matrix includes the
drug, and in FIGS. 3A and 3B, the drug is associated with the nanoshells.
FIGS. 4A and 4B illustrate embodiments that combine both features as drug
is in the polymer matrix and associated with the nanoshells. FIG. 5A
depicts an embodiment in which the drug forms a central core which is
surrounded by a shell of a polymer matrix including nanoshells. Although
the nanoshells illustrated in FIGS. 2B, 3B, 4B, and 5A are shown as
encapsulated in the polymer matrix, some of the nanoshells may not be
entirely surrounded by the polymer matrix and may be present at the
surface. Similarly, for a coating on an implantable medical device
including nanoshells, the nanoshells may be dispersed or embedded in the
coating, and some of the nanoshells may not be entirely surrounded by
polymer. Alternatively, an additional coating layer may be disposed over
the layer including the nanoshells such that all nanoshells would be
entirely or substantially surrounded by polymer.

[0094]For polymer matrices, such as those illustrated in FIGS. 2A, 2B, 4A,
and 4B, and a coating on a device, the polymer matrix may be a solid
solution in which the drug is dissolved, or essentially dissolved, or the
drug and polymer may form separate phases, or a combination thereof. The
polymer forms a continuous phase in the polymer matrix, and the drug, if
present as a separate phase, may form a co-continuous phase, or may form
discrete domains that do not connect to form a continuous network.
Preferably, the drug does not form a continuous phase. The drug may be
distributed uniformly or non-uniformly throughout the polymer matrix. The
ratio of polymer to drug, on a mass basis, may vary from about 1:1 to
about 10:1, preferably from about 2:1 to about 8:1.

[0095]Another non-limiting exemplary embodiment is shown in FIG. 5B which
depicts a nanoshell at the core, with a drug-rich inner shell, and an
outer shell of a polymer matrix which functions as a rate-limiting
membrane or layer. Similarly, a coating on a device may have one
drug-rich layer which may be referred to as a drug reservoir layer, and a
subsequent layer including the nanoshells disposed over the drug
reservoir layer, which may be referred to as a rate limiting layer. The
polymer forms a continuous phase in the rate limiting layer whether part
of a coating or a particle (such as illustrated in FIG. 5B). It is not
required that the polymer form a continuous matrix in the inner shell of
the embodiments of FIG. 5B, or in the drug reservoir layer of a coating
on a device, but the polymer or other material of the layer binds the
layer together and keeps it sufficiently attached to the layer or
substrate below. The mass percent drug in the inner layer or drug
reservoir layer may vary from about 5% to about 100%, that is, in some
embodiments, the inner layer or drug reservoir layer may be essentially
completely drug.

[0096]In some embodiments, a drug which may be the same as or different
from the drug of the inner layer or drug reservoir layer, may be added to
the outer layer or rate controlling layer.

[0097]If a drug is associated with the nanoshells, such as the embodiments
of FIGS. 3A, 3B, 4A, and 4B, the drug may be included in an outer coating
around the nanoshells. Alternatively, the nanoshells may have a core
including the drug with two outer shells, one outer shell having a lower
dielectric constant than the adjacent inner layer. In another alternative
embodiment, the core may include drug and a higher dielectric constant
material. For nanoshells with drug in the core, the outer layer would
need to be made from a material through which the drug can diffuse, or
made with pores, such as a porous metal. A non-limiting example is a
particle having a first shell, closest to the drug containing core, which
is a polymer that has semiconducting properties, or a polymer with
embedded material such as silica resulting in a dielectric constant
higher than that of the outer layer. The outer layer of the particle may
be a partial shell or a porous shell of metal, or a shell of a conducting
polymer through which the drug is able to diffuse. Coatings for
implantable medical devices may include nanoshells with drug associated
with the nanoshells as described above.

[0098]Coatings for implantable medical devices may comprise drug in any
type of formulation, such as particles, liposomes, etc., where the
particle, liposomes, etc. is free of nanoshells. Thus, in some
embodiments, a coating may comprise particles with a polymer, and
nanoshells in the coating separate from the drug-containing particles.
Embodiments encompass inclusion of the polymer having a transition in the
above range in the drug containing particles, in the coating, and both in
the particles and the coating.

[0099]The particles of the present invention may be from about 20 nm to
several micrometers in diameter. Preferably, the particles are 50 nm to
10 μm, and more preferably from 50 nm to 500 nm, and even more
preferably, from 50 nm to 250 nm in diameter.

[0100]The particles or coatings of the present invention include at least
one polymer. The polymer, or a segment thereof if it is a block
copolymer, has a glass transition temperature, Tg, or a crystalline
melting temperature, Tm that, when plasticized under physiological
conditions, is in the range of 40-60° C., preferably 40-50°
C., and more preferably 40-45° C. In some embodiments, the Tg
is that of a blend of polymers, or of a polymer plasticized with a
plasticizer, which may also be a drug. These temperatures are close to
body temperature, and thus heating to above the Tg or Tm will
not result in injury to tissue. As used herein, "plasticized under
physiological conditions" will refer to plasticization with water at a pH
of about 6.5 to 7.5 and a temperature of about 37° C.

[0101]In order to obtain triggered drug release, the polymer that is
affected by heat from the nanoshells either controls, or is a significant
factor in controlling, drug release from the particles or the coating.
Thus, if heating by the nanoshells results in raising the temperature of
the polymer above its Tg or its Tm, the drug release will
change if the polymer volume fraction in the polymer matrix is at or
above the percolation threshold, or forms a continuous phase. As an
example where a significant change in drug release would not be expected
is if the segment of a block copolymer that has a Tg or Tm in
the temperature ranges above forms discrete and discontinuous regions
within a matrix of the other segment which is not impacted by the heating
of the nanoshells. In such case, the drug diffusivity through the matrix
may not be significantly impacted by the heating from the nanoshells as
the continuous phase or matrix is unaffected by the heating.

[0102]In general, optimal performance is obtained if the volume fraction
of the polymer, or segment or portion of the polymer that undergoes
transition due to heating by the nanoshells is at or above the
percolation threshold so that a continuous phase is formed. Upon heating,
diffusivity changes as a result of the polymer, segments of a polymer, or
portions of the polymer melting or changing to a rubbery state, and drug
release may be increased if the diffusivity change occurs for a
continuous phase. Thus, the volume fraction of crystalline regions in a
semi-crystalline polymer with a Tm in one of the above ranges is
preferably at or above the percolation limit. For a semi-crystalline
polymer, the percolation threshold may be higher for small crystals. The
crystallinity of the semi-crystalline polymer may be at least 25%. In
some embodiments, the crystallinity may be at least 35%, at least 50%, or
at least 70%.

[0103]Likewise, the polymer, portion of a polymer blend, or segment of a
block copolymer, with a Tg in one of the above ranges is preferably
at or above the percolation limit. For a block copolymer, the segment
lengths may be long enough to form separate phases. In some embodiments,
it is a sum of volume fractions of crystalline regions with a Tm as
above and amorphous polymer or regions with a Tg as above that may
be at or above the percolation limit.

[0104]In some embodiments, the volume fraction of polymer, or portions of
the polymer with a Tg or Tm in one of the above ranges may be
about 30% or greater, preferably about 40% or greater, and more
preferably about 50% or greater of the polymer matrix.

[0105]In preferred embodiments, the volume fraction of the drug, if
present as a discrete phase is present at a volume fraction below its
percolation threshold. In preferred embodiments, if drug is present as a
drug-rich phase, as opposed to being dissolved in or homogeneously
blended with the polymer, the drug-rich phase is present at a volume
fraction below its percolation threshold. In some embodiments, the drug
rich phase is at least 30% by volume drug, preferably at least 40% by
volume drug, and more preferably, at least 50% by volume drug. There may
be multiple drug-rich phases.

[0106]If the amorphous regions of a semi-crystalline polymer in a blend
have a Tg below 40° C., it is preferred that it is not
present as a continuous phase. In other words, it is preferred that the
sum of the volume fractions of such regions is below the percolation
threshold. However, this is not required. Similarly, it is preferred, but
not required, that the sum of the volume fraction of drug and any other
soluble substances, which may include another drug, is lower than the
percolation threshold.

[0107]Biocompatible polymers may be used in manufacturing the particles or
coatings. The polymer may be biodegradable or biostable. Blend of
polymers, including blends of biodegradable or biostable polymers, may be
used. Poly(N-isopropylacrylamide) and copolymers thereof with acrylamide
are excluded.

[0109]The compositions of the present invention are useful for drug
delivery. The nanoshells may be "activated" to modulate drug release. As
used herein, the term "activated," when used with respect to nanoshells,
means that the nanoshells, or particles or coatings including nanoshells,
are exposed to electromagnetic radiation of the proper wavelength, or a
fluctuating magnetic field or microwave field, depending upon the type of
nanoshells, resulting in heating of the nanoshells. The hot nanoshells
heat the polymer of the composition and as a result the temperature of
the polymer exceeds its operative transition temperature (Tg or
Tm), that is, the one that is in the temperature ranges mentioned
above. Drug diffusion rates in polymers are higher above the glass
transition temperature of the polymer or in the polymer melt, and thus
the drug release rate increases. A burst release of the drug may be
triggered by activating the nanoshells.

[0110]The release of drug from the polymer particles or coatings of the
present invention does not occur all at once upon activation of
nanoshells. Therefore, the increased release may be triggered multiple
times, and a pulsatile release profile may be obtained. After the
nanoshells are activated, the release may gradually increase to a peak
and then slowly decrease. The increase in the release rate is not
necessarily the same each time the nanoshells are activated, and drug
depletion will lead to a decrease in the peak release rate after
activation as the number of times the nanoshells are activated increases.

[0111]It is understood that some drug may diffuse from a coating or
particles of this invention even when the nanoshells have not been
activated, and this release will be referred to as the "background
release rate" or the "background release profile." The background release
rate is impacted by the amount and the distribution of drug in the
particle or coating, and the extent of water diffusion into the polymer.
Activation of the nanoshells, however, will substantially increase the
rate of diffusion over this background rate. Embodiments of the present
invention encompass a peak release rate, after the activation of the
nanoshells, which is at least 10%, at least 20%, or at least 40% greater
than the background release rate.

[0112]A coating of this invention will contain a plurality of nanoshells
sufficient to be able to heat the polymer of the coating to a temperature
above its Tg or Tm. If drug-containing particles are used and
the particles include nanoshells, it is the intent of this invention that
each particle include at least one nanoshell. Due, however, to the
vagaries of fabrication, some particles may not contain nanoshell(s). A
composition in which substantially all the particles contain nanoshells
is within the scope of this invention. In some embodiments, a plurality
of particles of this invention will contain a sufficient number of
nanoshells to heat the polymer of substantially all the particles to a
temperature above its Tg or Tm. In fact, in some embodiments, the
plurality of particles intentionally includes some particles devoid of
nanoshells to provide the desired overall drug release profile.

[0113]Nanoshells that are activated at different wavelengths or by
different mechanisms may be included in the plurality of particles,
either within individual particles, and/or in different individual
particles of the plurality. The plurality may be a blend of particles of
different types. The types of particles may differ in the nanoshells
included within the particles, the polymer and/or drug used, the
structure of the particle, such as the various illustrated in FIGS. 2-5,
or the like. Likewise, nanoshells activated at different wavelengths or
by different mechanisms may be included in a coating.

[0114]In some embodiments, the particles include more than one drug. Thus,
embodiments encompass particles or coatings for which release of two or
more drugs is modulated. Specific non-limiting embodiments include
particles whether nanoparticles or microparticles, and coatings for the
dual drug release of both a statin drug and an anti-inflammatory drug, or
dual drug release of a statin drug and fenofibrate. The release of both
(or more than one) drug is activated or triggered by exposure to
electromagnetic radiation of the proper wavelength, and/or a fluctuating
magnetic field or microwave field, depending upon the type(s) of
nanoshells.

[0115]The compositions of this invention may also include other components
such as, but not limited to, wetting agents, lubricating agents, fillers,
plasticizing agents, surfactants, diluents, mold release agents, agents
which act as drug carriers or binders, anti-tack agents, anti-foaming
agents, viscosity modifiers, anti-oxidants, adhesion promoters, coupling
agents, residual levels of solvents, and any other agent which aids in,
or is desirable in, the processing of the material, or is useful or
desirable as a component of the final product.

[0116]A particularly useful additive is a radioopaque contrast agent which
would allow the particles or the coating to be visualized in vivo.
Examples include barium and calcium. With respect to the particles of the
present invention, the core of the nanoshells may include, at least in
part, a radioopaque material such as barium sulfate.

[0117]Polymeric particles of this invention may be classified as a "matrix
type" or "monolithic type," wherein the drug and polymer are
substantially homogeneously mixed or "reservoir type," or
"microencapsulated type" wherein the drug is contained in a core
surrounded by a rate-controlling membrane.

[0118]There are various methods that are well known in the art by which
the matrix type particles or reservoir particles can be manufactured.
Such methods include emulsion solvent evaporation methods, phase
separation methods, interfacial methods, extrusion methods, molding
methods, injection molding methods, heat press methods, coating or
layering processes, spray drying, electrospraying, membrane emulsion,
precision particle fabrication and so forth. Specific examples of
manufacturing processes for matrix type particles may be found in the
following U.S. Pat. Nos. 4,954,298; 6,528,093; 4,897,268; 4,293,539;
6,224,794; 7,060,299; and 7,048,947, each of which is incorporated by
reference herein. Specific examples for the manufacture of reservoir-type
particles may be found in the following U.S. Pat. Nos. 6,767,637 and
4,622,244, each if which is incorporated by reference herein. None of the
preceding exemplary art is intended, nor should it be construed, to limit
the present invention.

[0119]One method that is particularly suitable for the preparation of
particles of this invention is emulsion solvent evaporation. The first
step in such a method is dissolving the polymer in an organic solvent
that is immiscible in water. Typical concentrations for solutions are
about 5 w/w % up to about 10 w/w %, while typical concentrations for
dispersions are up to about 5 w/w %. Solvents include, but are not
limited to, methylene chloride, dichloromethane, chloroform, or ethyl
acetate. Next, an emulsion of the organic solvent phase in an aqueous
phase is created by ultrasonication. Typical organic solvent to aqueous
solvent ratios used are about 1:2 to about 1:20, and the aqueous phase
contains emulsifying agents. Non-limiting emulsifying agents include
polyvinyl alcohol, polyvinyl pyrrolidone, sodium lauryl sulfate, sodium
cholate, TWEEN 80® (sorbitan monooleate polyethenoxy ether), diacetyl
tartaric acid ester of mono-and di-glycerides, glycerol monostearate,
glycerol monooleate, glycerol behenate, lecitihin, monosodium phosphate
derivatives of mono and di-glycerides, phosphatidyl-choline,
stearylamine, and eoxycholic acid.

[0120]Subsequently, evaporation of the organic solvent is carried out at
atmospheric or under vacuum with continuous stirring of the emulsion. The
resulting particles are suspended in the aqueous solution. For the
incorporation of hydrophobic drugs, the drug is dissolved in the organic
phase which also includes the polymer. As result, the particles suspended
in the aqueous solution at the end of the process have the drug
encapsulated within.

[0121]The emulsion solvent evaporation method is slightly different when
the encapsulation of a hydrophilic drug in the particle is desired. Prior
to the formation of an emulsion, the hydrophilic drug is dissolved in an
aqueous solution including an emulsifying agent as described above. The
aqueous solution is then emulsified in the organic phase including the
polymer (the first step above) at a ratio of aqueous to organic phase in
the initial emulsion of about 1:2 to about 1:20. Here, in contrast to the
first situation, the organic phase is the continuous phase and the
aqueous drug-containing phase is the discrete phase. Then the same steps
are followed as outlined above resulting in the formation of a double
emulsion. An aqueous phase is emulsified in an organic phase which in
turn is emulsified in a second aqueous phase. In the second emulsion, a
typical ratio of the "organic phase" (actually the first emulsion) to the
aqueous phase is about 1:100 to about 1:500. Subsequently, the
evaporation occurs with continuous stirring as with the first situation.

[0122]For both emulsion solvent evaporation methods, more vigorous
stirring during the solvent evaporation phase generally leads to smaller
particle sizes. The solvent evaporation operation as well as other
operations may be performed at lower temperatures if necessary to avoid
degradation of a drug and/or denaturing of a protein or peptide. The
final step of removing the solvent may be accomplished by supercritical
fluid solvent extraction instead of evaporation.

[0123]Another method that is particularly suitable for the preparation of
particles is precipitation. This method involves dissolving the polymer
and drug in an organic phase which is miscible in water. The solution is
added to an aqueous solution containing a colloid stabilizer, a
non-solvent for the polymer and the drug, such that the polymer and drug
precipitate to form particles. The organic solvent is removed from the
particles by either evaporation or dialysis.

[0124]Spray drying may be used for form particles. Equipment to accomplish
spray drying is well known in the art. The polymer and the drug, and
optionally a surfactant to reduce particle aggregation, are dissolved or
dispersed in a solvent, preferably one with a high volatility.
Pressurized air or another gas is also used to atomize the solution or
dispersion that is sprayed into a heated chamber to quickly remove the
solvent and precipitate the particles. The particle size and other
characteristics can be optimized by adjusting the nozzle orifice size
and/or type of nozzle used, the flow rate of the solution, the air
pressure for the atomization, and the temperature at the spray nozzle, as
well as the temperature in the chamber. Solution viscosity may be
limiting so the polymer molecular weight is typically about 50 kDa or
less, but this is not required.

[0125]A particularly useful variation of the spray drying technique
involves laminar jet technology which can be combined with electrostatic
field, vibrating nozzle, and coaxial fluid (gas or non-solvent)
technology. A typical but not-limiting intensity of the electrostatic
field is 2-20 kV between the nozzle and a substrate below. A vibrating
nozzle allows a laminar jet of fluid to be broken into droplets.
Enhancing the electrostatic dispersion of solutions allows for the
production of small, highly charged droplets which results in spherical
particles. A typical nozzle vibration for a vibrating nozzle is 60 to 120
kHz.

[0126]Co-axial fluid technology involves two immiscible fluids. A central
fluid contains a drug and it is surrounded by an outer fluid flowing
through a concentric annulus. The flow of fluid is broken up to form
particles. An annular stream of a second fluid moving at a high velocity
can help to make particles smaller than the nozzle opening size (Berkland
et al., "Fabrication of PLG Mircrospheres with Precisely Controlled and
Monodisperse Size Distributions," Journal of Controlled Release, 73:
59-74 (2001)).

[0127]A variation of the co-axial fluid technology is precision particle
fabrication (Berkland et al., "Precision Polymer Microparticles for
Controlled Drug Delivery," American Chemical Society Symposium 897:
Carrier Based Drug Delivery, Chapter 14, pages 197-213, American Chemical
Society, 2004). A solution or dispersion of polymer and drug is sprayed
through a small nozzle to form a stable laminar jet. In addition to the
use of the annular fluid, acoustic energy provided by a piezoelectric
transducer which is driven by a wave generator, disrupts the jet thus
breaking it into droplets. The ratio of the volume average diameter to
the number average diameter for particles manufactured with this method
ranged from 1.002 to 1.015.

[0128]The methods of forming particles described above may be modified to
include nanoshells. The nanoshells may be dispersed in the organic
solvent of the emulsion solvent evaporation methods, spray drying,
precipitation or other methods. Such methods are more amenable for the
production of the embodiments in FIGS. 2B, 3B, and 4B, but precipitation
and spray drying methods may result in precipitation of polymer and drug
around a single nanoshell. For the embodiments with a single nanoshell in
the center, such as FIGS. 2A, 3A, and 4A, particle coating techniques may
be used such as, without limitation, a fluid bed with a Wurster insert.
Other coating methods known in the art may also be used.

[0129]For coatings on devices, the coating may be disposed over the
surface of an implantable medical device by any number of methods
including, but not limited to, electrostatic coating, plasma deposition,
dipping, brushing, or spraying. In a presently preferred embodiment a
coating solution is sprayed onto the device. The solution may include the
drug and polymer, either dissolved and/or dispersed in a solvent,
preferably an organic solvent. The nanoshells may be dispersed in the
solution. The spraying may be carried out by atomizing the solution and
spraying it onto the device surface while rotating and translating the
device underneath the spray nozzles following by rotation and translation
under a flow of gas, such as air or nitrogen that may be above room
temperature that is above 20° C. to 25° C. Multiple passes
underneath the spray nozzles and the gas may be required to obtain a
desired layer thickness. Subsequently, the device may be heated to remove
residual solvent. Generally a coating layer is the result of the
application of the multiple passes in one process before the device is
subjected to an operation for the removal of residual solvent, or before
a different coating formulation is disposed over the substrate. However,
one coating layer may vary in concentration of a substance, such as for
example, the drug, if the coating solution does not have the same ratio
of drug to other substances in all the passes. With respect to coating
layer thickness, it may be in the range of about 0.5 and about 10 μm,
or about 0.5 and about 7 μm, or as presently preferred, about 2 and
about 7 μm.

[0130]The compositions of the present invention can be used for systemic
or local drug delivery.

[0131]Systemic delivery involves the administration of a drug at a
discrete location followed by the dispersal of the drug throughout the
patient's body including, of course, to the target treatment site or
organ. In order to achieve a therapeutically effective amount of the drug
at the target site, it is usually necessary to administer an initial dose
substantially greater than the therapeutically effective amount to
account for the dilution the drug undergoes as it travels through the
body. Systemic delivery is carried out primarily in two ways:
introduction of the drug into the digestive tract (enteral
administration) or into the vascular system (parenteral administration),
either directly such as injection into a vein or an artery or indirectly
such as injection into a muscle or into the bone marrow. For the
particles of the present invention, enteral administration is not likely
to be used, but embodiments of the present invention encompass other
forms of systemic administration.

[0132]Local delivery comprises administration of the drug directly to the
target site. The initial dose can be at or very close to the
therapeutically effective amount. With time, some of the locally
delivered drug may diffuse over a wider region but such is not the intent
of localized delivery and the concentration of the diffused drug will
ordinarily be sub-therapeutic, i.e., too low to have a therapeutic
effect.

[0133]There are a number of techniques for local drug delivery. Local
delivery includes local needle injection that is injection by a needle at
the site. A drug delivery catheter may be used, that is a catheter
designed to deliver fluids to a vein or artery. The fluid may include a
plurality of particles of the present invention.

[0134]The plurality of particles may be delivered by a coated balloon.
Examples of two types of catheter balloons are shown in FIGS. 6 and 7. In
FIG. 6, the balloon has substantially a single diameter over its entire
length such that the full length of the balloon is in contact with the
luminal surface of the vessel. "Substantially" a single diameter is
illustrated in FIG. 6, where the ends 550 of balloon 520 are not
necessarily square so that the balloon does have a large number of
diminishing diameters at the ends as it curves down to join the catheter
tube but the major portion of balloon length 500 has substantially the
same diameter.

[0135]Dual balloons or multiple balloons may also be used as well as a
balloon having two different outside diameters, as illustrated in FIG. 7.
As shown in FIG. 7, at each end of the balloon is a first diameter, and
also potentially at any number of multiple point between the ends. The
first diameter is the diameter sufficient to place the balloon in contact
with the vessel wall. Each section of the first diameter is separated
from each other section of such diameter by a second diameter, which is
less than the inside diameter of the vessel and therefore does not
contact the vessel surface. Of course, use of the term "a second
diameter" is nominal; the point is that there are regions between the
first diameters that are not in contact with the vessel surface and the
diameters of those regions may be identical or all may be different. FIG.
7 illustrates wherein balloon 620 connected to catheter 400 has first
diameters 600, which contact vessel wall 100 and second diameters 650. In
other embodiments, there are multiple balloons, similar to the single
balloon illustrated in FIG. 6, arranged in a series along the catheter.

[0136]The particles may be coated on the exterior of a balloon by either
suspension coating that was discussed above, followed by either
lyophilization or exposure to a temperature above room temperature to
remove solvent. The particles may be dust-coated on the balloon. For
balloons with multiple sections contacting the vessel wall, the particles
may coat only those sections that are in contact with the vessel surface,
only those sections not in contact with the vessel surface, or both. The
ends of the balloon may be coated or left uncoated in either of the above
embodiments.

[0137]The particles of the present invention may be delivered by a
microporous balloon, which is a balloon made from a material with small
holes, or pores, formed in the material of the balloon. The fluid used to
inflate the balloon includes the particles which can flow through the
pores. The flow of the fluid including the particles through the pores
may be enhanced by increasing the fluid pressure. Similar to the coated
balloon, if the balloon has multiple sections in contact with the vessel
wall, only those sections in contact with the vessel wall may have pores,
or alternatively only the sections between the sections touching the
vessel wall may have pores, or both sections may have pores. The ends of
the balloon may be porous or devoid of pores in either of the above
embodiments.

[0138]Another manner of delivering the particles of the present invention
is a catheter including a needle or syringe for injection into the
tissue. FIGS. 8A and 8B depict an exemplary embodiment of a needle
injection catheter in the undeployed and deployed states, respectively.
The assembly includes a central guidewire tube 29 surrounded by drug
delivery lumens 22a and 22b. Drug delivery port 18 allows for delivery of
drug substances into delivery lumens 22a and 22b. Needles 26a and 26b and
tubes 27a and 27b are aligned parallel with central guidewire tube 29 in
FIG. 8A. However, as illustrated in FIG. 8B, after movement of drug
delivery port 18 in the direction of arrow 30, hollow needles 26a and 26b
are forced out at an angle, α>0, and held in this position by
tubes 27a and 27b. When needles 26a and 26b are forced out, the needles
can penetrate the tissue or the wall of the lumen, thus allowing
medication to be injected via injection port 18. After drug delivery is
complete, the delivery port 18 is pulled back (in a direction opposite to
that shown by arrow 30), thus allowing the hollow needles 26a and 26b to
return to their original position.

[0139]Some injection catheters utilize a balloon to deploy the needles.
One exemplary embodiment of an injection balloon catheter for
cardiovascular applications is that of U.S. Pat. No. 6,692,466. A
schematic drawing of the injection balloon catheter is shown in FIG. 9.
The catheter 300 has been inserted into a lumen whose walls are
represented by 340 in FIG. 9. The balloon 310 disposed on the catheter
300 is depicted in the inflated state. The catheter assembly includes an
inflation lumen which is used to inflate the balloon by supplying fluid
through the lumen.

[0140]As illustrated in FIG. 9, the needle is in fluid communication with
a delivery lumen. The end of the delivery lumen includes an exit notch
360. Inflation of the balloon pushes the needle exit notch 360 into the
tissue 340. Subsequently, the needle 320, which is in fluid communication
with a delivery lumen, can be pushed to puncture, or penetrate, the
tissue 340. The device includes a mechanism to control the depth of
needle penetration. The needle can be either pre-filled with the drug
formulation to be delivered, or can be coupled to dispensing means known
in the art, such as but not limited to, a syringe or fluid pump.

[0141]Another manner of local delivery of the particles of the present
invention is by use of an implantable device such as a stent. The
particles including the nanoshells may be included in a coating disposed
over the device. Such embodiments differ from disposing over a device
surface a coating of polymer, drug, and nanoshells because in the former
embodiment, the polymer, drug, and nanoshells are preformed into
particles that are subsequently coated onto the device. A metallic stent,
a polymeric stent, or a biodegradable stent, whether fabricated from a
biodegradable polymer, a bioerodable metal, or a combination thereof, may
be coated. Any type of stent may be coated including, without limitation,
a balloon expandable stent, or a self-expandable stent. The material of
the device is not limited. The particles may be coated onto the stent, or
other device, using similar techniques to those described above for
coating a balloon. The particles may be incorporated in a biodegradable
implantable medical device, such as a stent, or in a biodegradable
implant that is implanted into the tissue. If incorporated in a
biodegradable device or implant, the particles are released to the local
site as the device or implant degrades.

[0142]Embodiments including delivery of the particles via a coating on a
device, or via a biodegradable implant or device, encompass delivery of
the drug by drug diffusion through the coating or device into the
patient's body, and/or release of the particles form the device or the
coating with subsequent release of the drug from the particles. Thus, the
coating or device may be designed to quickly dissolve or erode, thus
releasing the particles from the device or coating such that the drug is
substantially or primarily released from the particles. In some
embodiments, not less than 70%, preferably not less than 80%, of the drug
is released after the particles are released from the coating.
Alternatively, the composition may be in a coating of a device that does
not erode or dissolve with the particles included primarily to allow for
modulation of release from the coating. If a coating includes nanoshells,
a polymer, and a drug, but these are not all present in particles, the
drug release is primarily due to diffusion through the coating.

[0143]Coatings of the present invention that include a polymer, a drug,
and a plurality of nanoshells, and the particles of the present invention
that also include a polymer, a drug, and one or more nanoshells, may be
combined. The drug, polymer, and type of nanoshell in the particles may
be the same or different from those of the coating. The material of the
device is not a limitation.

[0144]Other types of catheters, balloons, injection catheters, or devices
designed for local injection or administration may be used, as well as
other types of implants or implantable devices in addition to those
described herein. The embodiments of methods of treatment using the
plurality of particles of the present invention are not limited to those
exemplary devices described herein.

[0145]Once the particles have been administered to a patient (animal,
including a human) or the a medical device including nanoshells in a
coating and/or the body of the device has been implanted, the nanoshells
may be activated by exposure to electromagnetic radiation of the
appropriate wavelength, a fluctuating magnetic field, or a microwave
field. In preferred embodiments, the exposure is done internally, that is
via a catheter or the like, such that exposure is limited to the area of
treatment, thus avoiding injury to healthy tissue. As a non-limiting
example a light guide such as a fiber optic type wire or cable, may be
attached to a catheter to allow it to be maneuvered to the treatment
region, or it may form an integrated part of a catheter. The light guide
may be capable of providing electromagnetic radiation at the appropriate
wavelength, such as, without limitation, the near infrared.

[0146]However, extracorporeal activation is also encompassed in the
various embodiments of the invention. In particular, magnetic resonance
equipment may be used external to the body to activate the nanoshells.
Drug delivery from the compositions of the present invention may be
modulated by activation externally. The external activation may be
triggered or initiated via feedback from a diagnostic device. Such
coupling of a diagnostic device to the manner of external activation
allows for a self-regulated, externally modulated, on-demand,
non-invasive drug delivery system. Thus, some embodiments of the present
invention may be a drug delivery system including particles or coatings
as described above, a diagnostic device, and a an external manner of
activating at least some of the nanoshells of the particles and/or
coating. In some embodiments the system includes a diagnostic device
coupled to an external activation device.

[0147]The compositions of the present invention may be used to treat any
number of diseases and conditions depending upon the drug used. Some
non-limiting examples include vulnerable plaque, restenosis, peripheral
vascular disease, small vessel bifurcations and cancer. In some
embodiments, the self-regulated, externally modulated, on-demand,
non-invasive drug delivery systems described in the previous paragraph
may be used for cardiovascular applications as well as other
applications.

[0157]Examples of statins, a class of drugs that can reduce low density
lipoproteins, also referred to as "bad cholesterol," by means of blocking
an enzyme in the liver used to manufacture cholesterol. Non-limiting
examples of statins are lovastatin, simvastatin, atorvastatin,
fluvastatin, pravastatin, and rosuvastatin.

[0160]Other therapeutic drugs that may find beneficial use herein include,
again without limitation, alpha-interferon, genetically engineered
endothelial cells, dexamethasone, antisense molecules which bind to
complementary DNA to inhibit transcription, and ribozymes, antibodies,
receptor ligands such as the nuclear receptor ligands estradiol and the
retinoids, thiazolidinediones (glitazones), enzymes, adhesion peptides,
blood clotting factors, inhibitors or clot dissolving drugs such as
streptokinase and tissue plasminogen activator, antigens for
immunization, hormones and growth factors, oligonucleotides such as
antisense oligonucleotides and ribozymes and retroviral vectors for use
in gene therapy, antiviral drugs and diuretics.

[0161]While particular embodiments of the present invention have been
shown and described, it will be obvious to those skilled in the art that
changes and modifications can be made without departing from this
invention in its broader aspects. Therefore, the claims are to encompass
within their scope all such changes and modifications as fall within the
true spirit and scope of this invention.

Patent applications by Dariush Davalian, San Jose, CA US

Patent applications by John J. Stankus, Campbell, CA US

Patent applications by Syed F. A. Hossainy, Fremont, CA US

Patent applications by ABBOTT CARDIOVASCULAR SYSTEMS INC.

Patent applications in class Errodable, resorbable, or dissolving

Patent applications in all subclasses Errodable, resorbable, or dissolving